Heart failure continues to be a major health problem. Approximately four million persons in the U.S. population have heart failure. With a steadily aging population, four hundred thousand individuals experience new onset heart failure each year, with a five year mortality rate approaching fifty percent.
Rather than a single pathological entity, “heart failure” defines a clinical syndrome with many different etiologies that reflects a fundamental abnormality in effective mechanical performance of the heart, such that the heart is unable to meet the demands of the body. There are various forms of heart failure, including “forward” and “backward” heart failure. Backward failure, synonymous with congestive heart failure, is due to increase in venous pressure (i.e., increase in pressure in the veins that return blood to the heart) resulting from the inability of the heart to discharge its contents normally, leading to pulmonary and systemic congestion. By contrast, forward failure is caused by an inability of the heart to maintain normal tissue perfusion, resulting in fatigue, weakness, loss of weight, and impairment of cerebral function.
Hibernating Myocardium
“Hibernating myocardium” constitutes a significant fraction of forward heart failures, and it may or may not be accompanied by pulmonary or systemic congestion. This condition reflects localized depressed myocardial function as a result of chronic non-critical ischemia (hypoxia resulting from low blood supply). The degree of ischemia is not sufficient to produce necrosis (infarction), but it locally restricts myocardial oxygenation and fuel supply, such that a part of the myocardium becomes hypoactive or dormant. Hibernating myocytes remain viable but do not contribute to the pumping action of the heart. The severity of myocardial damage depends on the duration of hibernation. Eventually, the damage may become irreversible and may lead to heart failure when the extent of myocardial dysfunction is great enough to compromise cardiac performance and reduce the cardiac output; that is, ischemic cardiomyopathy may be the ultimate result of hibernating myocardium, if it is not treated appropriately.
Traditionally, hibernating myocardium has been treated by surgical revascularization through coronary bypass surgery or angioplasty. The inconvenience of surgery and the incidence of morbidity or restenosis associated with these techniques underscores the need for supplemental or alternative pharmacological intervention. Fath-Ordoubadi et al., Heart 82: 210-216 (1999) and Pagano et al., Curr. Opin. Cardiol. 14: 506-509 (1999). Effective pharmacological intervention would be especially useful where surgery is contraindicated, as in the case of mild hibernating myocardium, or where the patient's condition is considered too serious for surgery.
Congestive heart failure was first treated pharmacologically with vasodilators and inotropic agents, which increase cardiac muscle contractility. See WO 99/40788. While these drugs improved hemodynamics over the short term, recent studies have found a discrepancy between improved hemodynamics and clinical outcome. In fact, the only risk factor found predictive of morbidity associated with congestive heart failure is the plasma level of the catecholamine norepinepherine. Cohn et al., “Plasma norepinepherine as a guide to prognosis in patients with chronic congestive heart failure.” N. Engl. J. Med. 311: 819-823 (1984); Lahiri et al., J. Cardio. Pharm. 33 (Suppl. 3): S9-S16 (1999). Thus, in the case of congestive heart failure, long term administration of inotropic agents is contraindicated. The compounds most useful to treat congestive heart failure have proven to be ACE inhibitors, which have a vasodilating effect, and multi-functional β-blockers like carvedilol, which exert an anti-adrenergic effect. Lahiri et al. (1999).
Like congestive heart failure, there is evidence that administration of inotropic agents may worsen ischemia associated with hibernating myocardium. In one study, low level treatment with the inotrope dobutamine increased myocardial function in hibernating myocardium, but high levels of dobutamine increased myocardial demand to the point where it passed an ischemic threshold. Senioer et al., “Enhanced detection of myocardial ischaemia by stress dobutamine echocardiography utilising the ‘biphasis’ response of wall thickening during low and high dose dobutamine infusion.” J. Am. Coll. Cardiol. 26: 26-32 (1995). This and similar studies have raised questions about the long term benefit to mortality from inotropic agents, despite their short term hemodynamic benefit. In particular, it has been proposed that further increases in myocardial demand may enhance ishemia associated with hibernating myocardium, thereby exacerbating necrosis and apoptosis. Lahiri et al. (1999).
Accordingly, it has been suggested that inotropic agents also are contraindicated for hibernating myocardium, and that hibernating myocardium should be treated with the same non-inotropic, or anti-adrenergic, agents that are used to treat congestive heart failure. By analogy to congestive heart failure, it has also been suggested that high plasma levels of catecholamines, like norepinepherine, are deleterious to clinical outcome of hibernating myocardium, because of their inotropic properties. Lahiri et al. (1999).
As there are only a handful of agents known to have limited efficacy for the long term treatment of hibernating myocardium, there remains a strong need for new therapeutic agents which have the potential to revitalize hibernating cells. In particular, there remains a strong need to find agents that can reduce the plasma blood level of catecholamines.
Diabetic Cardiomyopathy
Patients with diabetes are at high risk for developing diabetic cardiomyopathy (DCM). The exact etiology of this disease remains controversial, in part because many myocardial abnormalities are associated with diabetes. DCM is clearly defined, however, as a reversible cardiomyopathy that occurs in the absence of coronary atherosclerosis. Bell, Diabetes Care 18: 708-714 (1995). DCM is further characterized by myocardial fibrosis, that can be partially attributable to ischemia. Id. Hypertension, also characteristic of diabetes, can aggravate fibrosis to the point where DCM can become a serious, even fatal, condition. Id.
This hypertension is at least in part due to an abnormal activation of the sympathetic nervous system. Pallab et al., Am. J. Physiol. 252: E734-739. Among the manifestations of this aberrant activation is an increase in the level of norepinepherine in the heart, as well as its altered metabolism by the heart. Id. High levels of catecholamines, such as norepinepherine, in the heart or circulation result in the development of DCM. The accompanying myocardial damage is believed to be in part caused by the oxidative breakdown products of norepinepherine. Id. An ideal anti-hypertension agent for the diabetic patient thus would reduce the activation of the sympathetic nervous system without worsening hyperglycemia or hypoglycemia. Presently, very few compounds provide these characteristics.